Studies have shown that exposure to a stressor can increase ethanol consumption. One of the potential modulators of this effect is neuropeptide Y (NPY), which is involved in the regulation of both anxiety-like behavior and ethanol consumption in rodents. Thus, increased NPY signaling has been shown to reduce ethanol consumption and anxiety-like behaviors. The experiments described in the present proposal are designed to test the guiding hypothesis that NPY plays a protective role against stress-induced increases of ethanol consumption. All of the proposed studies will use a complex stressor, which consists of saline injections followed by simultaneous exposure to a novel environment and noise. Specific aim 1 will use mutant mice lacking NPY or the NPY Y1 receptor to determine the role of NPY signaling in stress-induced increases in ethanol consumption. Specific aim 2 will utilize a neurotoxin that is conjugated to NPY to target and kill cells expressing Y1 receptors. This neurotoxin allows the study of blunted NPY signaling in specific brain regions and aim 2 will determine the role of NPY signaling in the amygdala and the lateral hypothalamus on stress-induced increases in ethanol consumption. Specific aim 3 will study the effects of NPY signaling on limited access ethanol consumption in mice with or without prior exposure to a stressor. Specifically, mutant mice lacking NPY (or wild-type controls) with a prior history of stress exposure will be given access to ethanol for 2-4 hours/day, beginning 3 hours into the dark cycle. These procedures, labeled drinking-in-the-dark (DID), induce high levels of ethanol consumption and physiologically relevant blood ethanol concentrations and are thought to model binge-like ethanol drinking. Results from the proposed studies will provide insight on the importance of NPY signaling in modulating stress-induced increases of ethanol consumption. Since stress disorders are comorbid with alcoholism and as stress can trigger relapse in abstinent alcoholics, results from the present research may provide insight into potential therapeutic targets aimed at treated alcohol abuse and alcoholism.